September 20, 2001

Presentation of a Case for Central Hypoadrenalism

By Dusty Hardman

Introduction:

I am a 33-year-old female with a 7-year-old son.  I have been fatigued and have had reoccurring infections including pneumonia.  This is not normal as I am an athlete who is aspiring become a professional athlete.  I maintain a healthy, balanced diet and eat quite a bit of Organic food.  During February of 2001, I developed bronchitis and a sinus infection that was treated with antibiotics.  At the end of February 2001, I developed pneumonia and was treated with antibiotics again.  Just prior to this extended illness (duration of approximately five weeks), I was exercising regularly, teaching Spin classes three times a week, weight lifting four times a week and skate skiing or doing more riding once or twice a week.  I worked up to this intensity of exercise over a period of a year and a half although I have always been quite active.  My fatigue has gotten progressively worse since February of 2001.

 

When this fatigue persisted beyond the normal recovery time of pneumonia, I had my thyroid tested.  Thyroid problems are a concern for me because my Mother has Hashimoto’s thyroiditis and my brother has been diagnosed as hypothyroid.  I exhibit many symptoms of hypothyroid, however my test results were normal. 

 

Because of my continued concerns about persistent fatigue and recurrent infection, I was referred to a doctor of Internal Medicine.  She did quite a few tests and my cortisol levels concerned her enough to order Standard Dose 250mcg Synacthen ACTH stimulation test.  I realize that 20% of all patients seeing a primary care physician list fatigue with a small percentage of those people actually having an underlying physical cause[1].  I do not feel that my problems are mental.  I think I am one of a small percentage with an underlying physical cause for my fatigue and low immunity.

 

My purpose in writing this document is to give a documented interpretation of the ACTH stimulation test and other blood work and test that have been done.  From the research I have done I do not agree that my test results were normal.  I would like to propose further testing, research options and/or treatment options for my condition.  Even if all of my test results are normal, my physical symptoms are a presentation of something abnormal and unacceptable going on in my body.  I am a proactive person, not a reactive person.  It is important to me to have my body functioning at an optimal level as opposed to merely existing in a sick, fatigued state barely accomplishing day-to-day activities.  I believe, from my research, that I have low adrenal reserve and below normal adrenal function due to pituitary or hypothalamic dysfunction.

 

Test Interpretations

ACTH Stimulation Test

The ACTH stimulation test was done on July 2, 2001 because my baseline cortisol level was 8 ug/dL (range of 6-23 ug/dL).  The 250 mcg Synacthen test with a baseline measurement of ACTH and 30 and 60-minute measurements of cortisol was the test was performed.  Please note:  AURP recommends testing baseline cortisol, 30-minute cortisol and 60 minute cortisol.[2] My results to this test have been interpreted as normal and boarder line abnormal.  From my research, I feel that my results were abnormal and an indication of central hypoadrenalism.

 

“The ACTH stimulation test examines adrenal responsiveness but may not examine the entire hypothalamic-pituitary-adrenal (HPA) axis…”[3] The ACTH stimulation test may not be reliable for assessing hypothalamic-pituitary disease, however, it can be a strong indicator of a problem with the HPA axis depending upon which cut off level is used for the 30 minute ACTH stimulation test.   This was determined in a study where 30 patients with known hypothalamic or pituitary disease were given the Insulin hypoglycemia test and the ACTH stimulation test.  A cut off 550 nmol/L for the ACTH stimulation test was only a 70% indicator of hypothalamic-pituitary disorders.  At 30 minutes, my response to the ACTH stimulation test was 433 nmol/L, well below the 550 nmol/L cut-off used in this test.  “The short Synacthen may be misleading if used as a screening test…”[4]

 

In “Defining the normal cortisol response to the short Synacthen test:  implications for the investigation of hypothalamic-pituitary disorders” in Clinical Endocrinology (Oxf) a normal cortisol response at 30 minutes was a cortisol range of 510 to 626 nmol/L (18.5-22.7 ug/dL) for men and women.  In addition, cortisol responses were gender dependent with females showing significantly higher responses regardless of the basal cortisol values[5].  My response was 433 nmol/L, which is nearly 20% below the low end of the normal range as determined in this study.  My cortisol response to exogenous ACTH stimulation was not normal and was worthy of follow up testing and or temporary hydrocortisone replacement therapy to see if there was an improvement in symptoms.

 

My ACTH stimulation test result of 433 nmol/L is an abnormal result of the test as defined by recent medical literature.  Abnormal cortisol rise during exogenous ACTH stimulation is indicative of adrenal hypofunction or problems further up the HPA axis.  “It is suggested that partial ACTH deficiency may prevent involution of the adrenal cortex and preserve the cortisol response to ACTH stimulation.[6]”  The adrenal hypofunction could have been caused by decreased stimulation of the adrenals by ACTH for an extended period of time.[7]  I say this because my ACTH level was 4 pg/mL  (range 6-58 pg/mL) the one time it was tested and my response to the Insulin hypoglycemia test was not normal.  Lack of ACTH production indicates a problem with either the hypothalamus or pituitary.[8]  The insulin hypoglycemia test results will be discussed in the next section. The ACTH stimulation test is not a reliable indicator of hypothalamic-pituitary problems because the adrenals can still function normally and give results in the ‘normal’ range despite the fact that they are not able to function normally without exogenous stimulation[9].

 

 

Insulin Induced Hypoglycemia Test

The Insulin Induced Hypoglycemia Test (ITT) was done to me on July 13, 2001 because the ACTH stimulation test results were worthy of further investigation.  The ITT is considered the ‘gold standard’ for assessing hypothalamic-pituitary function[10]. 

 

According to Basic & Clinical Endocrinology (BCE), if cortisol increases above 18 ug/dL after hypoglycemia occurs, there is a normal ACTH reserve[11].  My cortisol level at 20 minutes decreased from 20.7 ug/dL at baseline to 11.7 ug/dL.  I find it interesting that my baseline cortisol was only 20.7 ug/dL (within normal range of 3.1-22.4 ug/dL for 9:00 am basal cortisol measurement) despite the fact that I was very stressed about having this test done, I do not like needles and knew I was going to get stuck at least five times in a three hour period.  It was also quite stressful to see the reaction of the nurses when I presented myself for the test.  They congregated at the nurse’s station, discussing the test procedure from an endocrinology textbook [I will give them credit for being kind, caring and thorough with respect to the test protocol-especially for having the dextrose solution at hand].  A decrease in cortisol is NOT a normal reaction to hypoglycemia.  It is an indication of a hypothalamic or pituitary problem.

 

According to another source, “In 44 control subjects, the post-hypoglycemia cortisol levels were 18.0-30.0 mcg/100mL compared with less than 1.0-9.0 mcg/100mL in 22 patients with hypopituitarism.[12]”  My response of 11.7 ug/dL is undoubtedly closer to the numbers of the hypopituitary patients than the controls.  The indication being that either my hypothalamus or my pituitary is not functioning properly.

 

During the test, I became so hypoglycemic that I began loosing consciousness.  My serum glucose level was 19 mg/dL just prior to the nurses injecting me with dextrose.  The test was terminated due to my extreme reaction to the insulin.  Peak reaction to the insulin should have occurred at 20-35 minutes after insulin was administered[13].   BCE also states, “It [the ITT] should be used with caution in patients in whom diminished adrenal reserve is suspected, since severe hypoglycemia may occur….[14]”  The Merck Manual states, “Corticosteroid deficiency also leads to an extreme sensitivity to insulin… so that the blood sugar levels may fall dangerously low.[15]  In addition to my test results, loss of consciousness is an extreme reaction to hypoglycemia as is a blood sugar of 19 mg/dL.  I believe the insulin was measured at .1 units/kg.  My weight that day was approximately 120 pounds.  From the literature, this is an appropriate amount of insulin to administer to someone of my weight.[16]

 

In a study called, “Counter-regulatory hormone responses to insulin-induced acute hypoglycemia in hypopituitary patients,” 13 normal healthy subjects and 9 patients with hypopituitarism were given an infusion of insulin (0.1 Unit/kg body weight).  All but two hypopituitary patients with hypothalamic pathology recovered spontaneously from the hypoglycemia[17].  The journal abstract does not give a total of how many of the 9 hypopituitary patients had hypothalamic pathology.  This abstract is a good indicator of how unusual it is for hypoglycemia to not reverse itself.  Of the 21 people who were tested, the two persons with hypothalamic problems were the ones with adverse reactions to hypoglycemia.

 

By the way, my Growth Hormone reacted normally.  It rose from .7 ng/mL (range 0.0-5.0 ng/mL) to 12.8 ng/mL at 20 minutes.

Salivary Cortisol

My salivary cortisol levels were tested over a period of 24 hours on August 19, 2001.  They were taken at 8 am, 12 pm, 4 pm and 11 pm.  An ND, Dr. Rebecca Wynsome, prescribed this test.  The Lab that compiled the results was Diagnos-Techs, Inc.

 

The results of this test indicated depressed cortisol production over this 24-hour period.  My cortisol burden was 14 nM and the normal reference range was 23-42 nM.  This test indicates that my cortisol level is below normal when it should be at its highest level of the day (Circadian rhythm of cortisol[18]).  My cortisol remains below normal during the course of the day.  Low cortisol levels throughout the day could be a reason for fatigue and poor immune function.

 

“The salivary cortisol concentration is an excellent indicator of the plasma free cortisol concentration.[19]”  Salivary cortisol is not only an excellent indicator of plasma concentrations of cortisol in the circadian rhythm[20], salivary cortisol is reliable enough to use during dynamic endocrine testing[21].  If there is any doubt as to the accuracy of the salivary cortisol numbers above, I will be happy to submit to serum cortisol testing at the same intervals that the salivary cortisol was tested as a means of comparison.

Urinary Cortisol measurements

I discovered one journal article that compared basal cortisol levels with the 24-hour urinary cortisol levels.  This study determined the 24-hour urinary cortisol was a better indicator of the HPA axis functioning than a single 0900h plasma cortisol measurement.  “It is concluded that urinary cortisol excretion can safely replace the hypoglycemia and metrypone test for the detection of insufficient basal cortisol production in patients with hypothalamic and/or pituitary disorders.[22]”  This is quite a bold statement on the researcher’s part but it is an indication that 24 hour urinary cortisol could be better indicator than morning cortisol of HPA problems.  I returned my 24-hour urinary cortisol to the lab on September 19, 2001.  The results of this test will be one more piece to my health puzzle.  I theorize that the urinary cortisol levels will be comparable to the salivary cortisol levels.

 

Thyroid

Since May of 2001, my TSH has varied from 3.55 mU/L (7/13/01) to 1.07 uIu/ml (8/14/01).  Free Thyroxine has ranged from .9 ng/dL (5/13/01) to 1.36 ng/dL (7/13/01).  All of these values fall well within the normal range.  Antimicrosomal AB, TPO was 1.4 IU/mL (6/22/01), also within the normal range of 0.0 to 2.0 IU/mL.

 

It is interesting to note that my Total T3 was tested on 8/14/01 and the result was 66.8 ng/dL (range of 40-150 ng/dL).  The conversion of T4 to T3 “…produces about 80 percent of the active form of the hormone…”[23]  Perhaps, in light of my many hypothyroid symptoms (cold intolerance, dry skin and hair), my low normal T3 value is not normal for me.  “In addition, cortisol deficiency has secondary endocrine effects, e.g. glucocoritcoid-reversible hypothyroidism…[24]”

 

Discussion

Evaluation of suspected primary or secondary adrenocortical insufficiency

 

Figure 1.  “Evaluation of suspected primary or secondary adrenocortical insufficiency.  Boxes enclose clinical decisions and circles enclose diagnostic tests.”[25]

Discussion of Figure 1

Obviously potential adrenocortical insufficiency was suspected for the rapid ACTH stimulation test to be performed.  As I have documented above, the results of the ACTH stimulation test were abnormal.  My plasma ACTH was low.  According to this flow chart, secondary adrenocortical insufficiency should be suspected.  If one chooses to interpret my ACTH stimulation test as normal using data from old journal articles or text books, decreased ACTH reserve is not excluded because of my cortisol rise at 60 minutes but the insulin hypoglycemia test was abnormal.  Once again, secondary adrenocortical insufficiency should be suspected.

 

Also to further substantiate my hypothesis above, over a 24-hour period, my salivary cortisol was well below normal levels.  Extremely low salivary cortisol is indication a problem with my hypothalamic-pituitary-adrenal axis.

 

All of these test results coupled with my symptoms show either a need for further testing and/or steroid replacement therapy.  Further Testing and Treatment Options will be presented below.

 

Lack of Treatment

Hypoadrenalism, regardless of cause, is a dangerous and insidious problem.  The primary symptom of secondary adrenal insufficiency, fatigue, is shared by 100% of patients.[26]  The danger is that the patient will go without further testing because it is determined that the cause of fatigue is functional rather than organic.  Granted, it could be easy to confuse the symptoms of adrenal insufficiency with functional fatigue.  See Table 2-Distinguishing Organic and Functional Causes of Fatigue.

 

Table 2-Distinguishing Organic and Functional Causes of Fatigue.[27]

Characteristic Organic Functional Chronic (>6 mo)* - + Course Progressive Fluctuates Identifiable stressors - + Sleep disturbance +/- + Depressed mood Reactive or secondary Primary Activity related Worsens Improves Morning symptoms worse - + Abnormal physical findings + - Associated symptoms Fewer, specific Multiple, nonspecific Family structure Supportive Stressful Highlighted items apply to me.

 

Adrenal insufficiency is difficult to diagnose because of the lack of standardization in diagnosis protocol, its rarity and for those who have secondary adrenal insufficiency there is misunderstanding of presentation of the symptoms.  Primary and secondary adrenal insufficient patients display quite different symptoms.  Plasma ACTH levels usually range from 400-2000 pg/mL for primaries, secondaries have ACTH levels that range from 0-50 pg/mL and are usually less than 20 pg/mL.[28]  My ACTH level was 4 pg/mL on July 2, 2001.  Primaries appear tanned because of their high ACTH levels however, “Excessive pigmentation doesn’t occur when adrenal insufficiency is caused by pituitary or hypothalamus insufficiency, conditions in which the basic problem is a deficiency of corticotropin [emphasis added].”[29]  Primaries have Potassium and Sodium imbalances and secondaries electrolytes are usually remain normal.[30]  Primaries become hypotensive where secondaries only become hypotensive when symptoms become severe.  Additionally, primary Addisonians present with extreme weight loss[31] while hypopituitary patients present with weight gain.[32]  I am not overweight but I do not eat much over the course of the day (mostly protein) and I have gained weight in the last couple of months.  Table 3-Primary vs. Secondary Hypoadrenalism.

 

Table 3-Primary vs. Secondary Hypoadrenalism

 

Symptom	Primary Hypoadrenalism	Secondary Hypoadrenalism
Pigmentation	YES	NO
Serum ACTH	HIGH 400-2000 pg/mL	USUALLY UNDER 20 pg/mL
Electrolyte imbalance	YES K/Na	NO
Hypotension	YES	NO
Weight loss	YES, sometimes severe	NO, Weight Gain
Hypoglycemia	Usually only in children	SOMETIMES

 

 

“Because the symptoms may start slowly and be subtle, and because no single laboratory test is definitive, doctors often don’t suspect Addison’s disease at the outset.  Sometimes a major stress such as … [a] serious illness, makes the symptoms more obvious…”[33] (Remember, the onset of my symptoms was with pneumonia in February of 2001.) Lack of standardization and agreement in diagnosis of secondary hypoadrenalism is dangerous and misleading to the patient[34].  “There is no consensus on how the test is performed, and various time points and administration are used.”[35]  Most research test result standards are geared toward primary Addison’s disease.  It takes significant detective work and interest to discover that secondary Addison’s disease presents itself very differently yet with the same deadly consequences if left untreated.[36] 

 

Symptoms and how they might be related

I lactate.  My prolactin level is normal 5.6 ng/mL (range 1.2-29.9 ng/mL).  The onset of the lactation is something I am not able to determine.  I have pigmentation on my face that is in the same place with the same coloring as my “pregnancy mask” was when I was pregnant with Zane.  The onset of the pregnancy mask was with pneumonia in February of 2001.  Since February of 2001, I have spotting one week prior to my period.  Sometimes is heavier than others (I like to call it my mini-period).  My PMS has been severe.  I have been menstruating for almost 20 years; this is not normal for me.  “…menstrual changes can also be found in patients with Addison disease.”[37]  My fatigue has not abated since February of 2001; it has become increasingly more severe.  My fatigue limits my physical activity because of the exhaustion and decreased immune function it causes.

 

Further Testing

1. Pupillary light reaction
2. Deep tendon reflexes
3. Visual field testing-I will do this
4.  ACTH serum collected properly - centrifuged & iced

 

“The results of this study indicate that both SST [Conventional Dose Short Synacthen 250 mcg] and LDSST [Short Synacthen Test 1 mcg], at a cut-off of 600nmol/L [21.7 ug/mL] are safe for the purpose of clinical decision-making with regard to steroid replacement therapy in patients with pituitary disease[38].”

 

Hypoadrenalism, regardless of cause, can cause death if left untreated.